Published online 27 March 2008 | Nature | doi:10.1038/news.2008.696

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Prions picked up by tuning fork detector

Tiny resonators might make for quick and early prion tests.

Stuck on you: prions in saline solution will stick to the antibodies on this miniature 'tuning fork'.Courtesy of the researchers

Prions that cause disorders such as mad cow disease are notoriously difficult to detect in people or animals before symptoms arise. Now researchers are attempting to develop sensors that can detect prions by having them bind to a tiny ‘tuning fork’ that changes its tune when prions are present.

Prions are abnormally structured proteins that are able to convert normal proteins into the abnormal form. They are infectious and cause a number of neurodegenerative diseases. Historically, the only way to accurately detect the presence of prions in people has been to take a blood sample, inject it into a test animal, wait several months and then kill the animal and sample its brain tissue. Aside from being slow, expensive and somewhat grisly, this method is not particularly effective, with a correct diagnosis only 31% of the time.

There are concerns that some portion of the population might be harbouring infectious prions, with outbreaks of disease yet to come. A better method of prion detection is important for allaying peoples’ fears, as well as for screening blood banks to ensure they are clear of these abnormal proteins.

Within the past few years, researchers have discovered how to increase prion numbers from the blood of infected hamsters, so that they are easier to detect, and have found a resin that binds hamster prion proteins, allowing them to be physically removed from the blood. But it’s unclear whether this would work with human prions. Even if it did, a test based on boosting prion numbers would still take days to perform.

Ringing the changes

Now a team of biomedical engineers led by Harold Craighead at Cornell University in New York report on a different strategy for detecting prion prescence: nanoscopic resonators1. These small devices function like tuning forks — their resonance frequency changes as mass is added to them. Such devices are already used to detect the presence of bacterial pathogens, but prions are a bigger challenge as they are smaller, lighter and present in low concentrations in the blood.

The team made nanoscale resonators coated with commercially available antibodies that adhere to cow prions. They then exposed these resonators to prions in a saline solution. The prions stuck to the antibodies, but because they are so small, they barely changed the frequency of the resonator.

To amplify the effect, the Cornell team exposed the resonator to a second solution containing different antibodies that adhered to the prions already bound to the resonator. Exposure to a third solution, this time of metal-oxide particles, attached these bulky particles to the second set of antibodies. The heavier load of prions-plus-metal resulted in a much larger change in frequency in the resonator — enough to be noticeable.

Unlike other tests in development, once this technique is perfected it should provide an instantaneous result.

Bound in blood

The next step is to get these tests to work in blood rather than a saline solution. Blood contains a host of proteins and other chemicals, and making antibodies that selectively bind only the infectious prions will be tricky, but shouldn’t be impossible: other companies are working on this now.

“The real challenge is going to be to build an automated device that can take blood from a cow in the field and give a rapid response as to whether prions are present,” says Craighead. “At the moment we only test cows when they fall over, but that is a late stage of the disease. It would be ideal to test cows a lot earlier. Resonators could be one path to doing this.”

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“Since we can only detect prions reliably in the brains of dead people, having one more option available is definitely a good thing,” says neurologist Claudio Soto at the University of Texas Medical Branch in Galveston. “But the researchers need to improve sensitivity dramatically for this to work,” he says. Nano-engineer Thomas Thundat at Oak Ridge National Laboratory, Tennessee, who was not involved with the work, says that shouldn’t be a problem: “Getting more sensitive readings depends on increasing the resonance frequency of these devices, which is a straightforward engineering task that we are more than ready to do.”

“The results are very exciting,” he adds. “With this technology at hand we are now about two years away from having a prion detection solution.” 

  • References

    1. Varshney, M. et al. Anal. Chem. 80, 2141-2148 (2008). | Article | PubMed | ChemPort |
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